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Understanding connective tissue development and disease with PDGFR-driven.....

通过 PDGFR 驱动了解结缔组织发育和疾病......

基本信息

批准号：
8466513
负责人：
Lorin Olson
金额：
$ 34.44万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8466513
关键词：
Address Aneuploidy Biochemical Bypass Catalysis Cell Nucleus Cells Chromosome Segregation Chromosomes Complex Congenital Abnormality DNA Double Strand Break DNA Repair Pathway Defect Development Developmental Biology Diagnosis Disease Double Strand Break Repair Enzymes Eukaryota Exhibits Failure Generations Genetic Genetic Recombination Genome Goals Health Human Incidence Infertility Instruction Knockout Mice Mammals Mediating Meiosis Modeling Molecular Mus Oklahoma PDGFRB gene Pathway interactions Phenotype Plant Roots Play Positioning Attribute Property Proteins Regulation Role Sequence Homologs Single-Stranded DNA Sterility Structural Protein Structure System Testing Tissues Transgenic Mice Turner&apos s Syndrome Work base connective tissue development domain mapping ds-DNA homologous recombination in vivo insight prevent recombinase recombinational repair repaired segregation

项目摘要

PROJECT SUMMARY (See instructions): Homologous recombination is the only error-free system to repair DNA double-strand breaks. In meiosis, homologous recombination also provides temporal association between pairs of homologous chromosomes allowing their orderly segregation to opposite poles of dividing nuclei. This has a direct impact on faithful haploidization of a genome versus generation of aneuploidy. Indeed, failure of proper homologous chromosome segregation leads to infertility and severe aneuploid-based birth defects such as Down, Klinefelter, Edwards and Turner syndromes. At the center of the homologous recombination pathway is the step of strand invasion catalyzed by the ubiquitous Rad51 and the meiotic specific Dmcl recombinases. The proper functions of the recombinases require interaction with accessory proteins. Our central hypothesis is that two accessory proteins, Hop2 and Mndl, are essential for normal progression of homologous recombination and homologous chromosome segregation in mammalian meiosis. In part this may be explained by Hop2 and Mndl forming a heterodimer that stimulates strand invasion promoted by Dmcl and Rad51. In this proposal, we will use genetic and biochemical approaches to test this hypothesis and address fundamental questions about Mndl and Hop2 in higher eukaryotes: what are the structural determinants of the Hop2/Mnd1-Dmc1/Rad51 cooperation, and when and how do Mndl and Hop2 regulate the progression of homologous recombination in mammalian meiotic cells? Additionally, an important goal is to determine whether Hop2 by itself can function as a recombinase. If confirmed, our results will position Hop2 as the only ATP-independent meiotic recombinase and define a new pathway of DSB repair distinct from those promoted by Dmcl and Rad51. Through defining the roles of accessory proteins, the broader implication of our studies is to understand the contribution of homologous recombination in preventing homologous chromosome segregation defects leading to infertility and aneuploidy in humans.

项目总结（见说明）：同源重组是唯一无错误的DNA双链断裂修复系统。在减数分裂中，同源重组也提供了同源染色体对之间的时间关联，允许它们有序地分离到分裂核的相反两极。这对基因组的忠实单倍化与非整倍体的产生具有直接影响。事实上，正确的同源染色体分离的失败导致不育和严重的非整倍体为基础的出生缺陷，如唐氏综合征，克兰费尔特，爱德华兹和特纳综合征。同源重组途径的中心是由普遍存在的Rad 51和减数分裂特异性Dmcl重组酶催化的链侵入步骤。重组酶的正常功能需要与辅助蛋白相互作用。我们的中心假设是，两个辅助蛋白，Hop 2和Mndl，是必不可少的同源重组和同源染色体分离在哺乳动物减数分裂的正常进展。在某种程度上，这可以通过Hop 2和Mndl形成刺激由Dmcl和Rad 51促进的链侵入的异二聚体来解释。在这项提案中，我们将使用遗传和生物化学的方法来测试这一假设，并解决有关Mndl和Hop 2在高等真核生物的基本问题：什么是Hop 2/Mnd 1-Dmc 1/Rad 51合作的结构决定因素，以及何时以及如何Mndl和Hop 2调节哺乳动物减数分裂细胞中同源重组的进展？此外，一个重要的目标是确定Hop 2本身是否可以作为重组酶发挥作用。如果得到证实，我们的研究结果将Hop 2定位为唯一的ATP-独立的减数分裂重组酶，并定义一个新的DSB修复途径，不同于Dmcl和Rad 51促进的DSB修复途径。通过定义辅助蛋白的作用，我们的研究的更广泛的意义是了解同源重组在防止同源染色体分离缺陷导致人类不育和非整倍体的贡献。